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Jyosthna et al. World Journal of Pharmaceutical Research
DEVELOPMENT AND IN-VITRO EVALUATION OF PULSATILE
CORE IN CUP TABLET OF TORSEMIDE
Jyosthna Polishetti*1, Jyothsna Savula
2, Praveen Gogu
3 and Swetha G.
4
1,2
Marri Laxman Reddy Institute of Pharmacy, Dundigal, Qutbullapur, Hyderabad, 500043.
3Scientist at Dr. Reddy’s, FR&D, IPDO Global Oncology, Bhachupally, Hyderabad.
4Anwar-Ul-Uloom College of Pharmacy, Mallepally, Hyderabad.
ABSTRACT
Pulsatile systems are gaining a lot of interest as they deliver the drug at
the right site of action at the right time and in the right amount, thus
providing spatial and temporal delivery and increasing patient
compliance. Torsemide is used to reduce extra fluid in the body
(edema) caused by conditions such as heart failure, liver disease, and
kidney disease. The aim of the present work is to prepare and evaluate
pulsatile drug delivery system to increase the therapeutic efficacy of
torsemide. The drug torsemide is with short half life i.e.3.5 hrs and
when it is developed into core in cup type of tablet its half life is
extended to 12 hr and when compared to the other drugs like
furosemide which is modified to form torsemide is taken 200mg but torsemide is taken as
only 25mg with high solubility than furosemide. Core in cup tablet shows zero order kinetics
which is an advantage to this type of tablet. The concentration of soluble hydrophilic layer is
selected using 32 factorial designs. A typical pulsatile release is obtained from all the
formulation with no drug release in the lag time and the concentration of polymer on top
layer is a critical factor influencing the release pattern. The core-in-cup tablets were
compared with core only tablets and immediate release capsules.
KEYWORDS: Toresemide, pulsatile, core in cup, zero order kinetics, polymer, half life.
INTRODUCTION
Pulsatile systems are gaining a lot of interest as they deliver the drug at the right site of action
at the right time and in the right amount, thus providing spatial and temporal delivery and
increasing patient compliance. These systems are designed according to the circadian rhythm
World Journal of Pharmaceutical Research SJIF Impact Factor 7.523
Volume 6, Issue 5, 951-968. Research Article ISSN 2277– 7105
*Corresponding Author
Jyosthna Polishetti
Marri Laxman Reddy
Institute of Pharmacy,
Dundigal, Qutbullapur,
Hyderabad, 500043.
Article Received on
06 March 2017,
Revised on 26 March 2017,
Accepted on 16 April 2017
DOI: 10.20959/wjpr20175-8387
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of the body. The principle rationale for the use of pulsatile release is for the drugs where a
constant drug release, i.e., a zero-order release is not desired. The release of the drug as a
pulse after a lag time has to be designed in such a way that a complete and rapid drug release
follows the lag time. Torsemide is used to reduce extra fluid in the body (edema) caused by
conditions such as heart failure, liver disease, and kidney disease. This can lessen symptoms
such as shortness of breath and swelling in your arms, legs and abdomen. The drug is also
used to treat high blood pressure. Lowering high blood pressure helps prevent strokes, heart
attacks, kidney problem. Torsemide is “water pill” (diuretic) that causes you to make more
urine. This helps your body get rid of extra water and salt.
DESCRIPTION
Torsemide is a diuretic of the pyridine-sulfonylurea class. Its chemical name is 1-isopropyl-3-
[(4-m-toluidino-3-pyridyl) sulfonyl] urea and its structural formula is:
Torsemide was procured from Gland Pharma.
EXCIPIENTS
Microcrystalline Cellulose : Accent Microcel Industries, Paldi Kankaj.
Hydroxy propyl methyl cellulose : Corel Pharma Chem.
Formulation of Core and Cup Tablets
(i) Formulation of Core Tablets:
Core tablets were prepared by wet granulation method. Torsemide, HPMC K15, HPMC
K100, Lactose were dry mixed in a polybag for 5 min and then wet granulated with
magnesium stearate and talc as the binder in a hydro alcoholic granulating fluid of isopropyl
alcohol: water (9:1) to form granules. The granules were dried in a tray dryer at 60C for
sufficient time until the loss on drying (LOD) was not more than 3%. The dried granules
were passed through sieve no. 45 to form granules of uniform size. Finally colloidal silicon
dioxide was added and dry mixed and finally lubricated with magnesium stearate the loss on
drying was not more than 3%. The dried granules were first passed through mesh no. 45, to
obtain granules of uniform size. The granules were then lubricated with magnesium stearate.
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iii) Compression of Core-in-Cup Tablets: and evaluated for various physical properties
such as angle of repose, bulk density, tapped density, Carr’s index and Hausner’s ratio. Then
Core tablets composed of the active ingredient were punched on compression machine using
6 mm round, flat punches to form disc shaped core tablets.
ii) Formulation of Blend for the Hydrophobic Cup
Weighed quantities of sodium CMC and xanthum gum as per the batch size were dry mixed
in a polybag for 5 min and then wet granulated with a hydroalcoholic solution (Isopropyl
alcohol: water 9:1) of talc to form granules. These granules were dried in a tray drier at 60C
for an hour so that.
The disc shaped tablets of the active core were manually placed in the centre of a10 mm
larger round flat faced punch in the die cavity of the tablet press, before the addition of the
cup material and the machine was run until the lower punch moved down slightly. Weighed
quantity of the blend for the cup was manually poured into the die cavity using a spatula and
the gap between core tablet and die was filled with other materials like polymers, finally
compressed to produce the desired core in cup tablet. The formulation for preparation of core
and cup are depicted
Table-1: Formulation of F1 –F6 Torsemide tablets
CORE
Batch No. F1 F2 F3 F4 F5 F6
Ingredient Qty
(mg/ Tab)
Qty
(mg/ Tab)
Qty
(mg/ Tab)
Qty
(mg/ Tab)
Qty
(mg/ Tab)
Qty
(mg/ Tab)
Torsemide 25 25 25 25 25 25
Lactose 60 50 40 60 50 40
HPMC-P 15 10 20 30 -- -- --
HPMC-P 100 -- -- -- 10 20 30
Magnesium Stearate 2 2 2 3 3 3
Talc 3 3 3 2 2 2
Total weight 100 100 100 100 100 100
CUP
Na CMC 100 100 100 100 100 100
Xanthum gum 5mg 5mg 5mg 5mg 5mg 5mg
Isopropyl alcohol Q.S Q.S Q.S Q.S Q.S Q.S
Magnesium stearate 1% 1% 1% 1% 1% 1%
Talc 1% 1% 1% 1% 1% 1%
Total tablet weight 250 mg 250 mg 250 mg 250 mg 250 mg 250 mg
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Figure-1: Core in cup tablet
EVALUATION TESTS
PREFORMULATION EVALUATION TESTS
Determination of Bulk density and Tapped density
An accurately weighed quantity of the powder (W), was carefully poured into the graduated
cylinder and the volume (V0) was measured. Then the graduated cylinder was closed with lid,
set into the density determination apparatus. The density apparatus was set for 100 taps and
after that, the volume (Vf) was measured and operation was continued till the two consecutive
readings were equal. The bulk density and tapped density were calculated using the following
formulae
Bulk density = W / V0
Tapped density = W / Vf
Where, W = Weight of the powder
V0 = Initial volume
Vf = Final volume
Compressibility Index or Carr’s Index (CI)
It indicates the ease with which a material can be induced to flow. The Compressibility Index
(Carr’s Index) is a measure of the propensity of a powder to be compressed. It is determined
from the bulk and tapped densities. In theory, the less compressible a material, the more
flowable it is. As such, it is a measure of the relative importance of inter-particulate
interactions. In a free-flowing powder, such interactions are generally less significant and the
bulk, taped densities will be closer in value. For poorer flowing materials, there are
frequently greater inter-particle interactions and a greater difference between the bulk and
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tapped densities will be observed. These differences are reflected in the Compressibility
Index which is calculated using the following formula:
Hausner’s Ratio
Hausner’s ratio was measured by the ratio of tapped density to bulk density.
Angle of Repose (θ)
The frictional forces in a loose powder can be measured by angle of repose, θ. This is the
maximum angle possible between the surface of a pile of powder and the horizontal plane.
The powder mixture was allowed to flow through the funnel fixed to a stand at definite
height. The angle of repose was then calculated by measuring the height and radius of the
heap of the powder formed.
The fixed funnel method was employed to measure the angle of repose. A funnel was secured
with its tip at a given height (h), above a graph paper that is placed on a flat horizontal
surface. The blend was carefully poured through the funnel until the apex of the conical pile
just touches the tip of the funnel. The radius (r) of the base of the conical pile was measured.
The angle of repose (θ) was calculated using the following formula:
Tan θ = h/r
θ = tan-1
(h/r)
Where, θ = angle of repose, h = height of the pile in cms, r = radius of the pile
DRUG – EXCIPIENT INTERACTION STUDIES (FT-IR)
Infrared spectroscopy is one of the most powerful analytical techniques when it comes to the
determination of presence of various functional groups involved in making up the molecule.
It provides very well accountable spectral data regarding any change in the functional group
characteristics of a drug molecule occurring in the process of formulation. IR spectra of
Torsemide and its formulations were obtained by KBr pellet method using FT-IR Shimadzu
ST EQ-025 Spectrophotometer in order to rule out drug-carrier interaction occurring during
the formulation process.
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DIFFERENTIAL SCANNING CALORIMETRY (DSC) STUDIES:
In order to investigate the possible interaction between Torsemide, HPMC K15, HPMC
K100, Lactose differential scanning calorimetry (DSC) analysis was carried out on pure
substances and their physical mixtures (PM) in equimolar ratios using the Perkin Elmer
Thermal Analyzer instrument equipped with a computerized data section. Samples (3-4 mg)
were placed in an aluminium pan and heated in an aluminium pan and heated at a rate of
10.00⁰c/min with indium in the reference pan in an atmosphere of nitrogen at a rate of 50.0
ml/min to a temperature of 200.00⁰c.
POST FORMULATION EVALUATION TEST OF THE TABLETS
Hardness
Hardness of the tablet is defined as the force applied across the diameter of the tablet in the
order to break the tablet. The resistance of the tablet to chipping, abrasion or breakage under
condition of storage transformation and handling before usage depends on its hardness. For
each formulation, the hardness of 6 tablets was determined using a Monsanto hardness tester.
It is expressed in Kg / cm2.
Friability (F)
It is a measure of mechanical strength of tablets. The friability of the tablet was determined
using Roche Friabilator. It is expressed in percentage (%).It should be preferably between o.5
to 1.0%. 10 tablets were initially weighed (Winitial) and transferred into the friabilator. The
friabilator was operated at 25 rpm for four mins. The tablets were weighed again (Wfinal). The
percentage friability was then calculated by:
Weight Variation
Twenty tablets were selected randomly from the lot and weighed individually to check the
weight variation. IP limit for weight variation in case of tablets weighing up to 80 mg is ±
10%.
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Table-2: Pharmacopoeial specifications for tablet weight variation
Average weight of
Tablets (mg) (I.P)
Average weight of
Tablets (mg) (U.S.P)
Maximum percentage
difference allowed
Less than 80
80 – 250
More than 250
Less than 130
130 – 324
More than 324
10
7.5
5
Thickness
Tablet thickness is an important characteristic in reproducing appearance. Twenty tablets
were taken and their thickness was measured by Vernier callipers. It is expressed in mm.
Content Uniformity
For determination of drug content three tablets from each formulation were weighed
individually, crushed and diluted to 100ml with sufficient amount of purified water. Then
aliquot of the filtrate was diluted suitably and analyzed spectrophotometrically at 288 nm
against blank. The drug content of each formulation was evaluated as per the standard
protocol ranges between 99-101%w/v.
Disintegration Time
The Invitro disintegration time was determined using disintegration test apparatus. A tablet
was placed in each of the six tubes of the apparatus and one disc was added to each tube. The
time in seconds or minutes taken for complete disintegration of the tablet in distilled water
with no palpable mass remaining in the apparatus was measured.
Dissolution Profile of the Tablets
Dissolution of Torsemide tablets was studied using USP type 2 paddle dissolution test
apparatus (Labindia) employing paddle stirrer. 900 ml of 0.1 N HCL (1.2 pH), 6.8 pH
phosphate buffer were used as dissolution medium. The stirrer was adjusted to rotate at 50
rpm and a temperature of 37±0.5⁰c in 6.8 pH phosphate buffer for 24h. The dissolution
samples of 10ml were withdrawn at sampling intervals 1, 2, 4, 6, 8, 10, 12 hours. The
dissolution media was replenished with 10ml of pH 6.8 phosphate buffer after each withdrawl
and analyzed for Torsemide by measuring the absorbance at 288 nm.
Table-3: Parameters for Invitro dissolution study
Invitrodissolution study was carried out in USP dissolution test apparatus type 2
(paddle)
Dissolution medium 6.8 pH phosphate buffer
Volume of dissolution medium 900 ml
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Temperature 37 ± 0.5⁰c
Rotation speed 50 rpm
ƛmax 288 nm
RESULTS AND DISCUSSION
Six formulations of core in cup tablets of Torsemide were developed by preparing core
tablets using Lactose as diluent and xanthum gum as a binder and different grades of HPMC
polymer as a release retardant in different proportions in core formulation. The core tablets
and Cup material was prepared by wet granulation method.
IR spectra
The compatibility evaluations were performed by FTIR spectroscopy analysis. The study
implies that the drug and polymers are compatible with each other. There were no interaction
found between polymers and drug.
PRE FORMULATION STUDIES
Bulk density and tapped density for the formulations were in the range of 0.442- 0.485
gm/ml & 0.537 – 0.593 gm/ml. Compressibility index and Hauser’s ratios were in the range
of 16.8-18.7 % and 1.10-1.28. From results of the trial batches almost all Formulation trials
showed good flow properties. The results obtained confirm that all the batches which exhibit
good flow properties have good packing characteristics. Pre-formulation results are
mentioned in the table no:
POST COMPRESSION PARAMETERS
Thickness of tablets was found to be almost uniform in all the six formulations. They were
found to be in the ranges of 3.2 -3.3 mm. All the tablets passed weight variation test as the %
weight variation, which was within the pharmacopoeial limits of ± 5% of the weight. The
average weight of all tablet formulations was within the ranges of 245-251mg. The weights
of all the tablets were found to be almost uniform. The measured hardness of tablets of each
batch of all formulations was ranged between 5.0-6.0 Kg/cm2, which is falling within the
hardness specification as per I.P. The friability of tablets was found to be within the ranges
between 0.38 to 0.64%, which are generally considered and acceptable as per I.P. The data
indicates that the percentage friability was less than 1% in all the formulations ensuring no
physical damage will be take place during handling and shipping of tablets. The results
indicate that the percentage of drug content was within the ranges of 97.2 to 100.6% of
Torsemide which was within the acceptable limits as per the I.P. Trial (F2) is taken as
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optimized formulation batch, since all the parameters are found to be within limits when
compared with all formulations.
In Vitro Dissolution Studies
Dissolution of Torsemide tablets was studied using USP type 2 paddle dissolution test
apparatus (Labindia) employing paddle stirrer. 900 ml of 0.1 N HCL (1.2 pH), 6.8 pH
phosphate buffer were used as dissolution medium. The stirrer was adjusted to rotate at 50
rpm and a temperature of 37±0.5⁰c in 6.8 pH phosphate buffer for 24h. The dissolution
samples of 10ml were withdrawn at sampling intervals 1, 2, 4, 6, 8, 10, 12 hours. The
dissolution media was replenished with 10ml of pH 6.8 phosphate buffer after each withdrawl
and analyzed for Torsemide by measuring the absorbance at 288 nm, after filtering the
solution through 0.45 μm millipore filters. Concentration was determined from the standard
plot of Torsemide and finally the results were plotted as cumulative % drug release versus
time graphs.
Among all the formulations, F2 shows 99.54% drug release in 12 Hrs. Optimized
formulations (F2) of Torsemide core in cup tablets was compared with Marketed product.
Kinetic data for optimized formulation
The kinetic treatment of the drug release data of the prepared formulations followed zero
order drug release; the prepared formulations followed Hixson crowell plot, as the plot
showed high linearity (R2 = 0.949) indicating errosion as one mechanism of drug release. F2
showed high linearity in Higuchi plot (R2 = 0.972) and the Korsmeyer -Peppas plot (R2
=0.994) and the slope value “n” was 0.024. The relative complexity of this formulation and
its components may indicate that the drug release is controlled by more than one process. The
result from the Peppas equation indicates that a combination of diffusion and erosion may be
the mechanism of release.
Stability Studies of Optimized formulations
Stability Studies of Optimized formulation from the results shown in graphs, it can be
inferred that the physical appearance of the tablets, remained unchanged at the end of 30, 60
& 90th day for at room temperature and at 400C±200C/75±5% RH for 90days. Results show
no change in physical appearance and invitro dissolution. Hence Optimized formulation was
found stable at tested temperature.
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Calibration curve
Table-4 & Fig: 2: Determination of ƛmax of Torsemide in pH phosphate buffer
Wavelength Absorbance
220 0.223
240 0.247
245 0.252
260 0.278
288 0.295
300 0.212
Table -5 & Fig: 3: Standard calibration curve absorbance in 6.8 pH phosphate buffer
at 288nm
Concentration
(mcg) Absorbance (nm)
0 0
0.0112 0.277
0.0168 0.419
0.0224 0.553
0.0280 0.693
0.0336 0.830
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RESULTS
Table-6: Evaluation of Pre-Formulation Parameters of Core in cup torsemide Tablet
Blend
Formulation
Code
Angle of
Repose ± S.D Bulk Density
Tapped
Density
% Carr’s
Index
Hausner’s
Ratio
F1 29.56 ± 0.46 0.485 0.593 18.2 1.10
F2 27.12 ± 0.13 0.460 0.556 17.2 1.21
F3 30.35 ± 0.35 0.478 0.575 16.8 1.24
F4 32.12 ± 0.84 0.450 0.554 18.7 1.28
F5 30.65 ± 0.35 0.442 0.537 17.6 1.27
F6 31.25±0.23 0.456 0.550 17.0 1.20
Figure-4: FT-IR of Pure Torsemide
Table-7: Evaluation of disintegration time of Torsemide formulation (F2):
S.no Disintegration
time (minutes)
1 55 ± 0.11
2 56 ± 0.15
3 58 ± 0.21
4 60 ± 0.18
5 60 ± 0.18
6 62 ± 0.17
Average
disintegration time 58.5 ± 0.29
Table-8: Evaluation of Post-Compression parameters of Torsemide tablets
Formulation
Code
Hardness
(kg/cm2)
Average
weight of 20
tablets (mg)
Friability
(%)
Thickness
(mm)
Drug Content
± S.D (%)
F1 5.5 245.5 ± 0.56 0.64 3.2 98.6 ± 0.61
F2 6.0 247.3 ± 0.64 0.54 3.2 99.9 ± 0.58
F3 5.0 246.6 ± 0.25 0.58 3.2 97.2 ± 0.28
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F4 5.0 251.3 ± 0.35 0.45 3.2 99.9 ± 0.70
F5 5.5 247.8 ± 0.33 0.38 3.2 100.6 ± 0.74
F6 5.5 249.2± 0.42 0.62 3.3 99.8 ± 0.35
Table-9 & Fig: 5: Invitrodrug release from Torsemide formulations (F1-F3)
Time in
HR's F1 F2 F3
0 0.00 0.00 0.00
0.5 10.23 17.93 24.90
1 25.44 29.66 43.08
2 36.88 40.87 54.99
4 42.90 58.54 69.87
6 53.88 72.45 83.03
8 64.90 84.23 91.99
10 76.65 92.94 100.00
12 89.66 99.54 100.00
F1=……
F2=……
F3=……
Table 10 & Fig-6: Invitro drug release from Torsemide formulation (F4-F6)
Time in
HR's F4 F5 F6
0 0.00 0.00 0.00
0.5 11.98 24.87 29.76
1 21.76 39.76 43.98
2 32.09 51.89 58.54
4 43.90 65.43 70.75
6 54.54 76.98 81.53
8 65.95 91.87 94.89
10 79.07 100.00 100.00
12 93.98 100.00 100.00
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F4=……
F5=……
F6=……
Table-11& Fig-7: Zero-order plot of Torsemide formulation (F2):
TIME F2
0 0.00
0.5 17.93
1 29.66
2 40.87
4 58.54
6 72.45
8 84.23
10 92.94
12 99.54
Table 12 & Fig-8: First-order plot of Torsemide formulation (F2)
TIME F2
0 0.0
0.5 0.3
1 0.8
2 1.2
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4 1.4
6 1.5
8 1.8
10 1.9
12 2.0
Table-13 & Fig-9: Higuchi Plot of Torsemide formulation (F2)
Table-14 & Fig-10: Korsmeyer & Peppas plot of Torsemide formulation (F2)
log time F2
0.0 1.0
0.3 1.3
0.5 1.5
0.6 1.6
0.7 1.8
0.8 1.9
Root T F2
0.707107 6.850467
1 9.58181
1.414214 11.8651
2 15.0765
2.44949 17.379
2.828427 19.2152
3.162278 20.518
3.464102 21.5443
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0.8 1.9
0.9 2.0
1.0 2.0
Table 15 & Fig-11: Hix crowell Plot of Torsemide (F2)
Table-16: Stability data of Torsemide Formulation (F2) at 40±2⁰C/75±5%RH
S. No. Time in
days
Physical
changes
% Drug Content ± SD
(40±2⁰C/75±5%RH)
1. 01 -- 98.64 ± 0.82
2. 30 No change 98.00 ± 0.30
3. 60 No change 97.35 ± 0.51
4. 90 No change 97.09 ± 0.40
TIME F2OR2
0.5 2.61734
1 3.095449
2 3.444569
4 3.882853
6 4.168817
8 4.383513
10 4.52968
12 4.641589
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Table-17 & Fig-12 Comparative Dissolution Profiles of Optimized Batch (F-2) With
Innovator
Comparision of Marketed and optimized Formulation Dissolution Profiles
CONCLUSION
From the above experimental results it can be concluded that core in cup tablets of Torsemide
can be prepared by using different proportion & combination of excipients and selected F2 as
best formulation based on desired drug release profile. The core-in-cup technology is a
potential technology, which can control the release of highly water soluble drugs for Twice-a-
Time (hrs) Innovator F2
0 0 0
1 1.40 0
2 17.95 15.20
4 36.15 21.63
6 50.85 42.56
8 74.63 65.44
10 89.25 85.90
12 99.97 99.54
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day administration with the use of a combination of hydrophilic and hydrophobic polymers.
This technology has already proved successful for sparingly soluble drugs and with this study
proves potential for developing a system capable of delivering highly water soluble drugs that
follow zero- order release kinetics.
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